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Intrinsic transition of embryonic stem-cell differentiation into neural progenitors

Abstract

The neural fate is generally considered to be the intrinsic direction of embryonic stem (ES) cell differentiation. However, little is known about the intracellular mechanism that leads undifferentiated cells to adopt the neural fate in the absence of extrinsic inductive signals. Here we show that the zinc-finger nuclear protein Zfp521 is essential and sufficient for driving the intrinsic neural differentiation of mouse ES cells. In the absence of the neural differentiation inhibitor BMP4, strong Zfp521 expression is intrinsically induced in differentiating ES cells. Forced expression of Zfp521 enables the neural conversion of ES cells even in the presence of BMP4. Conversely, in differentiation culture, Zfp521-depleted ES cells do not undergo neural conversion but tend to halt at the epiblast state. Zfp521 directly activates early neural genes by working with the co-activator p300. Thus, the transition of ES cell differentiation from the epiblast state into neuroectodermal progenitors specifically depends on the cell-intrinsic expression and activator function of Zfp521.

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Figure 1: The early neuroectodermal gene Zfp521 strongly promotes neural differentiation in ES cell culture.
Figure 2: Zfp521 expression pattern in early mouse embryos.
Figure 3: Zfp521 is required for early neural differentiation of ES cells.
Figure 4: Zfp521 is required to advance the differentiation step from the epiblast-like state into the early neuroectodermal state.
Figure 5: Zfp521 is directly involved in the activation of early neuroectodermal genes and functions together with the co-activator p300.
Figure 6: Summary of Zfp521’s role in the initiation of neural differentiation.

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Gene Expression Omnibus

Data deposits

Microarray data have been deposited in GEO under accession number GSE25593.

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Acknowledgements

We are grateful to H. Niwa for comments; M. Okada for advice on the GeneChip study; Y. Toyooka-Kamiya for constant encouragement and technical advice; H. Akimaru for advice on the shRNA knockdown study; and members of the Sasai laboratory for discussion and advice. This work was supported by grants-in-aid from MEXT, the Kobe Cluster Project and the Leading Project (Y.S.).

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Contributions

Y.S. designed the research and D.K. performed the majority of mES cell experiments with technical help from S.B., M.K. and R.Y. N.S., M.O., H.I. and K.W. collaborated with D.K. in the ChIP, hES cell, Xenopus and SFEB experiments. H.K. and K.N. performed the blastocyst injections and L.M.J. and S.-i.N. helped GeneChip screening.

Corresponding author

Correspondence to Yoshiki Sasai.

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The authors declare no competing financial interests.

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Kamiya, D., Banno, S., Sasai, N. et al. Intrinsic transition of embryonic stem-cell differentiation into neural progenitors. Nature 470, 503–509 (2011). https://doi.org/10.1038/nature09726

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